Abstract
Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant condition in which mutations in the transthyretin gene cause amyloid fibrils to develop and deposit into tissues, affecting primarily the nerves and heart causing polyneuropathy and cardiomyopathy respectively. Standard treatment has been liver transplants to try and eliminate the mutated transthyretin products as the liver is the main source of transthyretin production. A new drug named inotersen (brand name Tagsedi), also known as IONIS-TTRRX, has been approved by the United States Food and Drug Agency, Health Canada, and European Commission in 2018, and introduced to the market for patients in stage 1 and stage 2 hATTR polyneuropathy. Inotersen is a second-generation antisense oligonucleotide with 2′-O-methoxyethyl modification designed to bind to the 3′ untranslated region of the transthyretin mRNA in the nucleus of the liver cells. By doing so, it prevents the production of the mutant and wild-type forms of transthyretin, impeding the progression of the disease. In this article, the mechanism of action and safety profile of inotersen will be discussed along with some future directions following its approval.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Palladini G, Merlini G (2016) What is new in diagnosis and management of light chain amyloidosis? Blood 128(2):159–168. https://doi.org/10.1182/blood-2016-01-629790
Sekijima Y (2015) Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry 86(9):1036–1043. https://doi.org/10.1136/jnnp-2014-308724
Gertz MA (2017) Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care 23(7 Suppl):S107–S112
Gertz MA, Benson MD, Dyck PJ et al (2015) Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol 66(21):2451–2466. https://doi.org/10.1016/j.jacc.2015.09.075
Mathew V, Wang AK (2019) Inotersen: new promise for the treatment of hereditary transthyretin amyloidosis. Drug Des Devel Ther 13:1515–1525. https://doi.org/10.2147/DDDT.S162913
Buxbaum JN (2018) Oligonucleotide drugs for transthyretin amyloidosis. N Engl J Med 379(21):2086. https://doi.org/10.1056/NEJMc1810994
Johnson SM, Connelly S, Fearns C et al (2012) The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. J Mol Biol 421(2–3):185–203. https://doi.org/10.1016/j.jmb.2011.12.060
Adams D, Gonzalez-Duarte A, O’Riordan WD et al (2018) Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 379(1):11–21. https://doi.org/10.1056/NEJMoa1716153
Keam SJ (2018) Inotersen: first global approval. Drugs 78(13):1371–1376. https://doi.org/10.1007/s40265-018-0968-5
Mickle K, Lasser KE, Hoch JS et al (2019) The effectiveness and value of patisiran and inotersen for hereditary transthyretin amyloidosis. J Manag Care Spec Pharm 25(1):10–15. https://doi.org/10.18553/jmcp.2019.25.1.010
Gales L (2019) Tegsedi (inotersen): an antisense oligonucleotide approved for the treatment of adult patients with hereditary transthyretin amyloidosis. Pharmaceuticals (Basel) 12(2). https://doi.org/10.3390/ph12020078
Adams D, Suhr OB, Dyck PJ et al (2017) Trial design and rationale for APOLLO, a phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol 17(1):181. https://doi.org/10.1186/s12883-017-0948-5
Al Shaer D, Al Musaimi O, Albericio F et al (2019) 2018 FDA tides harvest. Pharmaceuticals (Basel) 12(2). https://doi.org/10.3390/ph12020052
Summers JS, Shaw BR (2001) Boranophosphates as mimics of natural phosphodiesters in DNA. Curr Med Chem 8(10):1147–1155
Ackermann EJ, Guo S, Benson MD et al (2016) Suppressing transthyretin production in mice, monkeys and humans using 2nd-generation antisense oligonucleotides. Amyloid 23(3):148–157. https://doi.org/10.1080/13506129.2016.1191458
Benson MD, Kluve-Beckerman B, Zeldenrust SR et al (2006) Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve 33(5):609–618. https://doi.org/10.1002/mus.20503
Benson MD, Dasgupta NR, Rissing SM et al (2017) Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy. Amyloid 24(4):219–225. https://doi.org/10.1080/13506129.2017.1374946
Benson MD, Waddington-Cruz M, Berk JL et al (2018) Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 379(1):22–31. https://doi.org/10.1056/NEJMoa1716793
Lu QL, Liang HD, Partridge T, Blomley MJ (2003) Microbubble ultrasound improves the efficiency of gene transduction in skeletal muscle in vivo with reduced tissue damage. Gene Ther 10(5):396–405
Yu RZ, Grundy JS, Geary RS (2013) Clinical pharmacokinetics of second generation antisense oligonucleotides. Expert Opin Drug Metab Toxicol 9(2):169–182. https://doi.org/10.1517/17425255.2013.737320
Geary RS (2009) Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin Drug Metab Toxicol 5(4):381–391. https://doi.org/10.1517/17425250902877680
NIH US National Library of Medicine : Open-Label Extension Assessing Long Term Safety and Efficacy of IONIS-TTR Rx in Familial Amyloid Polyneuropathy (FAP). https://clinicaltrials.gov/ct2/show/NCT02175004. Accessed 11 July 2019
Adams AM, Harding PL, Iversen PL et al (2007) Antisense oligonucleotide induced exon skipping and the dystrophin gene transcript: cocktails and chemistries. BMC Mol Biol 8:57
Echigoya Y, Nakamura A, Nagata T et al (2017) Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 114(16):4213–4218. https://doi.org/10.1073/pnas.1613203114
Lu QL, Rabinowitz A, Chen YC et al (2005) Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proc Natl Acad Sci U S A 102(1):198–203. https://doi.org/10.1073/pnas.0406700102
Ezzat K, Aoki Y, Koo T et al (2015) Self-assembly into nanoparticles is essential for receptor mediated uptake of therapeutic antisense oligonucleotides. Nano Lett 15(7):4364–4373. https://doi.org/10.1021/acs.nanolett.5b00490
Walker I, Irwin WJ, Akhtar S (1995) Improved cellular delivery of antisense oligonucleotides using transferrin receptor antibody-oligonucleotide conjugates. Pharm Res 12(10):1548–1553
Echigoya Y, Aoki Y, Miskew B et al (2015) Long-term efficacy of systemic multiexon skipping targeting dystrophin exons 45-55 with a cocktail of vivo-morpholinos in mdx52 mice. Mol Ther Nucleic Acids 4:e225. https://doi.org/10.1038/mtna.2014.76
Wen Shen, Cheryl L. De Hoyos, Michael T. Migawa, Timothy A. Vickers, Hong Sun, Audrey Low, Thomas A. Bell, Meghdad Rahdar, Swagatam Mukhopadhyay, Christopher E. Hart, Melanie Bell, Stan Riney, Susan F. Murray, Sarah Greenlee, Rosanne M. Crooke, Xue-hai Liang, Punit P. Seth, Stanley T. Crooke, (2019) Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index. Nature Biotechnology 37(6):640–650
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Mahfouz, M., Maruyama, R., Yokota, T. (2020). Inotersen for the Treatment of Hereditary Transthyretin Amyloidosis. In: Yokota, T., Maruyama, R. (eds) Gapmers. Methods in Molecular Biology, vol 2176. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0771-8_6
Download citation
DOI: https://doi.org/10.1007/978-1-0716-0771-8_6
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-0770-1
Online ISBN: 978-1-0716-0771-8
eBook Packages: Springer Protocols